The hosts have gone four games without a win and face Mauricio Pochettino's men who have lost just twice in their last 10 Premier League games
This year's continental adventure ended in disappointment as Thursday's 2-2 draw against Benfica saw the Londoners crash out of the Europa League 5-3 on aggregate at the last-16 stage.
And their Champions League qualification hopes look all but over this season too, with Tim Sherwood's men seven points adrift of fourth-placed Manchester City having played three games more.
With a sixth-placed finish likely to secure Europa League football next season after City's Capital One Cup triumph, Sherwood's charges are on course to be in Europe's secondary club competition once more.
|9/2||Emmanuel Adebayor is 9/2 to score the first goal when Spurs face Southampton with Betway|
However, a poor recent run of form - they are winless in four in all competitions - has heightened speculation that Sherwood's position may not be safe.
Tottenham have lost three of their last four Premier League games, scoring just one goal in the process, and face a tough trip to in-form title contenders Liverpool next weekend.
Sherwood left the likes of Emmanuel Adebayor, Jan Vertonghen, Hugo Lloris and Paulinho at home for the midweek trip to Portugal, with the quartet all expected to feature on Sunday.
Mauricio Pochettino's Southampton, meanwhile, can still harbour slim European ambitions of their own, although they would have to overhaul Manchester United, Everton and Tottenham to qualify.
Southampton also have the advantage of a full week's rest going into the game - unlike their opponents - and Pochettino's team head to White Hart Lane having lost just twice in their last 10 top-flight outings.
They won last time out on the road when Jay Rodriguez's goal earned them a 1-0 victory at Crystal Palace, and they will be hoping for a change of fortune from the reverse fixture in December, when Tottenham won 3-2 at St Mary's in Sherwood's first league game in charge.
Adebayor scored twice that day, but Pochettino knows Sherwood has plenty of quality at his disposal.
"They have Adebayor, but they also have Soldado and I can name many players that they have in their team who are quality players that can decide a game on their own," he told reporters.
"They have a lot of good players that can do that. It's clear that when we played against them at St Mary's, Adebayor made things very difficult for us and this week we’ve been working on having all of their players under control, not just him."
Pochettino also revealed a number of injury concerns for the visitors, including Uruguayan playmaker Gaston Ramirez (knock), who played an hour in the 4-2 win over Norwich City last time out.
Jack Cork (ankle), Victor Wanyama, Morgan Schneiderlin, Guly do Prado and Kelvin Davis (all knocks) are also doubtful, although Dejan Lovren is expected to be fit after suffering a groin injury in the Norwich game.